Partial blockage of the blood vessels leading to the heart is one cause of heart disease. More severe blockage of blood vessels often leads to hypertension, ischemic injury, stroke, or myocardial infarction. Vascular occlusion is typically preceded by vascular stenosis which can be the result of intimal smooth muscle cell hyperplasia. One underlying cause of intimal smooth muscle cell hyperplasia is vascular smooth muscle injury and disruption of the integrity of the endothelial lining. Occlusive coronary atherosclerosis remains the major cause of mortality and morbidity in industrialized countries.
Arterial intimal thickening after injury is the result of the following series of events: 1) initiation of smooth muscle cell (SMC) proliferation within hours of injury, 2) SMC migration to the intima, and 3) further SMC proliferation in the intima with deposition of matrix (Clowes, et al., 1989). Investigations of the pathogenesis of intimal thickening following arterial injury have shown that platelets, endothelial cells, macrophages and smooth muscle cells release paracrine and autocrine growth factors (such as platelet derived growth factor (PDGFa), epidermal growth factor, insulin-like growth factor, and transforming growth factor and cytokines that result in the smooth muscle cell proliferation and migration (Ip, et al.). T-cells and macrophages also migrate into the neotima (Haudenschild; Clowes, 1985; Clowes, 1989; Manderson; Forrester). This cascade of events is not limited to arterial injury, but also occurs following injury to veins and arterioles. The overall disease process can be termed a hyperproliferative vascular disease because of the etiology of the disease process.
Vascular injury causing intimal thickening can be broadly categorized as being either biologically or mechanically induced. One of the most commonly occurring forms of biologically mediated vascular injury leading to stenosis is Atherosclerosis. The migration and proliferation of vascular smooth muscle plays a crucial role in the pathogenesis of atherosclerosis. Atherosclerotic lesions include massive accumulation of lipid laden "foam cells" derived from monocyte/macrophage and smooth muscle cells. Formation of "foam cell" regions is associated with a breech of endothelial integrity and basal lamina destruction. Triggered by these events, restenosis is produced by a rapid and selective proliferation of vascular smooth muscle cells with increased new basal lamina (extracellular matrix) formation and results in eventual blocking of arterial pathways (Davies).
Mechanical injuries leading to intimal thickening result following balloon angioplasty, vascular surgery, transplantation surgery, and other similar invasive processes that disrupt vascular integrity. Although balloon angioplasty can dilate arterial stenosis effectively, restenosis occurs in 30-40% of patients after 6 months (Califf, et al., 1990). Intimal thickening following balloon catheter injury has been studied in animals as a model for arterial restenosis that occurs in human patients following balloon angioplasty. De-endothelialization with an intraarterial catheter, which dilates an artery, injures the innermost layers of medial smooth muscle and may even kill some of the innermost cells (Schwartz; Fingerle; Clowes, 1975, Ferns, 1989, Reidy, 1988).
Injury to the innermost layers of medial smooth muscle is followed by a proliferation of the medial smooth muscle cells, after which many of them migrate into the intima through fenestrae in the internal elastic lamina and proliferate to form a neointimal lesion.
Typically, vascular stenosis can be detected and evaluated using angiographic or sonographic imaging techniques (Evans) and is often treated by percutaneous transluminal coronary angioplasty (balloon catheterization). Within a few months following angioplasty, however, the blood flow is reduced in approximately 30-40 percent of treated patients as a result of restenosis caused by a response to mechanical vascular injury suffered during the angioplasty procedure (Pepine; Hardoff).
In an attempt to prevent restenosis or reduced intimal smooth muscle cell proliferation following angioplasty, numerous pharmaceutical agents have been employed clinically, concurrent with or following angioplasty. Most pharmaceutical agents employed in an attempt to prevent or reduce the extent of restenosis have been unsuccessful. The following list identifies several of the agents for which favorable clinical results have been reported: lovastatin (Sahni; Gellman); thromboxane A.sub.2 synthetase inhibitors such as DP-1904 (Yabe); eicosapentanoic acid (Nye); ciprostene (a prostacyclin analog) (Demke; Darius); trapidil (a platelet derived growth factor) (Okamoto); angiotensin converting enzyme inhibitors (Gottlieb); low molecular weight heparin (de Vries); and 5-(3'-pyridinylmethyl)-benzofuran-2-carboxylate (Gorman, et al.; Payne, et al.; Wynalda, et al.; Graham, et al.).
The use of balloon catheter induced arterial injury in a variety of mammals has been developed as a standard model of vascular injury that will lead to intimal thickening and eventual vascular narrowing (Chevru; Fishman; Clowes, 1983; Clowes, 1991). Many compounds have been evaluated in this standard animal model in an attempt to develop better agents for preventing or reducing smooth muscle proliferation and intimal thickening.